Chronic diseases such as chronic hearing loss, tinnitus, hyperacusis, presbycusis, or balance disorders are often associated with noise- and/or age-related cochlear synaptopathy and vestibular synaptopathy in the patients that is independent of hair cell loss. For example, Kujawa et al., J. Neurosci., 29:14077-14085 (2009) and Lin et al., JARO, 12:605-616 (2011) demonstrated that noise-induced inner hair cell neurite loss (e.g., synaptopathy) can be extensive despite a normal hair cell complement in mouse and guinea pig models of mild noise trauma. This mechanism likely contributes to hearing disorders caused by noise injuries or cumulative age-related hearing loss (e.g., presbycusis).
Sergeyenko et al., J. Neurosci., 33:13686-13694 (2013) demonstrated that cochlear synapse loss progresses from youth to old age and is seen throughout the cochlea long before age-related changes in thresholds or hair cell counts in a mouse model of presbycusis. Moreover, Makary et al., JARO, 12:711-717 (2011) demonstrated that, in aging human ears with full complements of hair cells, mean spiral ganglion cell losses (SGCs, i.e., cochlear neurons) reach about 30% at 95 years, indicating that neurodegeneration can precede and/or occur independently of hair cell loss. Furthermore, in a related study in humans, Viana et al., Hear Res., 327:78-88 (2015) provided evidence that cochlear synaptopathy and the degeneration of peripheral nerve axons occur independently of hair cell loss and likely contribute to presbycusis. These types of diffuse synapse or SGC loss, although they may not necessarily affect hearing thresholds, contribute to processing difficulties and hearing in a noisy environment or lead to related maladaptive sequelae such as tinnitus or hyperacusis. Cochlear synaptopathy and the functional consequences thereof are also described in Schaette et al., J. Neurosci., 31:13452-13457 (2011); Wan et al., Hear Res., 329:1-10 (2015); and Liberman et al., PLoS One, 11(9):e0162726 (2016).
Blast injuries to the ear are very common in modern military operations due to improvised explosive devices (IEDs), which can cause sensorineural hearing loss and tinnitus. Tinnitus and hearing loss are the most prevalent adverse medical conditions reported among veterans with service-connected disabilities. Blast exposures can also induce injuries to the central auditory system, and persistent oxidative stress is believed to play a fundamental role in this pathophysiological response.
Tauopathies and cochlear neurodegeneration share oxidative stress as a common pathophysiological correlate and potential propagator of ongoing damage. More specifically, several studies have revealed that oxidative stress acts as a direct catalyst for inducing both hyperphosphorylation and aggregation of Tau. This correlation is further supported by work in superoxide dismutase 2 null mice, which exhibit constitutive hyperphosphorylation of Tau under conditions of chronic oxidative stress as an early postnatal pathological event that can be efficiently mitigated by high-dose catalytic antioxidant treatment. Consistent with this mechanistic vantage point, therapeutically-targeting oxidative stress using antioxidants has proven to be ameliorative among a broad spectrum of Tauopathies.
Further, Selkoe, Science, 198:789-791 (2002) observed that Alzheimer's disease begins with hippocampal synaptic dysfunction prior to neuronal degeneration, that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid beta protein, and that at least one mouse line had shown the impairment to be caused by a significant reduction in synaptic number. Sheng et al., Cold Spring Harb Perspect Biol, 4:a005777 (2012) discussed two major themes of pathogenesis of Alzheimer's disease. First, oligomeric Ab species have strong detrimental effects on synapse function and structure, particularly on the postsynaptic side; and second, decreased presenilin function impairs synaptic transmission and promotes neurodegeneration. In addition, Goldstein et al., Sci. Transl. Med., 4(134):doi:10.1126/scitranslmed.3003716 (2012) reported evidence of chronic traumatic encephalopathy (CTE) in wild-type C57BL/6 mice 2 weeks after exposure to a single blast, that was similar to the CTE neuropathology observed in American football players, and disclosed that blast-induced persistent hippocampal-dependent learning and memory deficits correlated with impaired axonal conduction and defective activity-dependent long-term potentiation of synaptic transmission. These observations highlight the importance of synaptogenesis and neuritogenesis for treatment of Alzheimer's disease, CTE and other central nervous system diseases.
Therefore, a need exists for methods of enhancing synaptogenesis and neuritogenesis in patients suffering from cochlear synaptopathy or vestibular synaptopathy or a central nervous system disease or condition, in particular cochlear synaptopathy or vestibular synaptopathy associated with chronic hearing loss, tinnitus, hyperacusis, presbycusis, or balance disorders. Also, the neurodegeneration and Tau protein aggregation (e.g., caused by blast exposure) highlights another need for methods of reducing neurodegeneration and Tau protein accumulation or aggregation.